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Construction of Arterial Occlusive Disease Animal Model

a construction and occlusive disease technology, applied in educational models, medical science, diagnostics, etc., can solve the problems of high mortality within a relatively short period, lack of stable pathologic conditions, and high probability of death, and achieve stable pathologic conditions, low animal mortality, and high certainty of vascular embolism.

Inactive Publication Date: 2008-11-27
HEALTH SCI TECH TRANSFER CENT JAPAN HEALTH SCI FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]It is an object to be attained by the present invention to develop a method for generating a cardiac infarction model which has a small variation in the degree of occlusion and a low level of animal mortality and provides stable pathologic conditions. Furthermore, it is another object to be attained by the present invention to develop a method for generating a vascular embolus animal model which has a high certainty of vascular embolus formation and subsequent ischemia and a small variation in their degree and is capable of selective and quantitative analysis. Also in the present invention, it is a problem to be solved by the present invention to develop a method for generating a vascular embolus animal model which gives low invasiveness and causes minor damage to animals.
[0010]Specifically, the present inventors have found that a cardiac infarction model which has a reduced animal mortality and is stable can be generated by ligating a blood vessel downstream of an arterial site to be occluded and subsequently subjecting to complete occluding of the artery at the site to be occluded.
[0011]Moreover, the present inventors have found that by employing an angiographic apparatus in delivering an autologous blood clot coagulated with a coagulating agent into an artery to form an embolus, an artery can be selectively occluded with the blood clot at a desired site within an animal, thereby generating an arterial embolus animal model in which the above-described problems have been solved.
[0014]According to the present invention, there are provided methods and kits for generating cardiac infarction animals, which allow complete occluding of trunk arteries, have a low animal mortality, and provide stable pathologic conditions. In addition, according to the present invention, there are provided methods for generating vascular embolus animal models, which have a high certainty of vascular embolus and a small variation in its degree and are capable of quantitative analysis. Employing the methods of the present invention will diminish invasiveness to animals and also reduce animal damage.

Problems solved by technology

Regarding conventional models of cardiac infarction, as methods for generating cardiac infarction models, for example, ligature of coronary artery with thoracotomy is commonly employed, but conventional ligature causes fibrillation directly after the procedure and has an extremely great likelihood of leading to death.
Major problems of these procedures are that occlusion is at varied degrees, non-occluded or incompletely occluded cases also take place, and these are lacking in providing stable models of pathologic conditions.
In addition, a high mortality within a relatively short period (for example, one month after the procedure) is also problematic.
Arterial embolus leads to various diseases and disorders, but it cannot yet be said that methods for treating these diseases and disorders have been established.
Especially, with respect to therapeutic treatments in its acute stages, agents, such as thrombolytics and nueroprotectives, are expected to be effective, but many of these agents have failed in clinical trials and a very small number of agents have been found to be effective.
Although models by cerebral trunk arterial occlusion are conventionally known as representative models of ischemia in medium- and large-sized animals, many of such models have disordered sites that are limited to the basal nucleus of the brain and there are few models which can give rise to damage in the cortex of the brain that is most discussed as sites causing cerebral function disorders in clinical situations.
However, these models lack in procedures for their exact injection into intracranial arteries of interest and identification and for evaluating ischemia, and thus result in variations in the distribution of cerebral ischemic portions and pathologic conditions, making it difficult to conduct selective and quantitative experiments.
As mentioned above, conventional vascular embolus procedures suffer from disadvantages of having a low certainty and varied degrees of vascular embolus and ischemia after the formation of vascular embolus and lacking in quantitiveness.
In addition, theses procedures give high invasiveness to animals and have a disadvantage of causing great damage to animals.

Method used

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  • Construction of Arterial Occlusive Disease Animal Model
  • Construction of Arterial Occlusive Disease Animal Model
  • Construction of Arterial Occlusive Disease Animal Model

Examples

Experimental program
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example 1

Generation of a Pig Model of Chronic Cardiac Infarction

[0040]Male pigs weighing 20-25 kg were used. After anesthesia, pigs were fixed in the recumbent position with the left chest up and an anticoagulant, heparin, was administered at 100 IU / kg, followed by thoracotomy by dissection between the third and fourth ribs. Subsequently, portion beyond the second branch of the anterior descending branch was exposed and completely ligated with a suture (see arrow B of the left panel in FIG. 1). (Complete ligating at this site does not give rise to fibrillation, leading to no death. This local ischemic treatment results in the tolerance to ischemia in the entire cardiac muscle.) After that, portion of the anterior descending branch which was proximate to the bifurcation of the circumflex branch and the anterior descending branch was exposed and a xylocalne jelly was applied to the blood vessel to prevent vascular spasm associated with the treatment, followed by placement of an ameroid ring (a...

example 2

Studies on Coagulating Agents, Conditions, and Others

[0044]As coagulating agents, ADP and thrombin were used to examine the degree of coagulation. ADP was used at concentrations of 30 and 100 μg / ml (without thrombin at both concentrations), and thrombin at concentrations of 0.5 and 10% (w / v) (without ADP at both concentrations). Blood was drawn from the ventral tail artery of a crab-eating macaque, and was placed into a catheter with or without adding a coagulating agent, incubated for 24 hours at 37° C., and then pushed out to observe the condition of coagulation. As control was used a sample to which neither of the coagulating agents was added (blood which was coagulated alone). The results were shown in the left panel of FIG. 3. It was found that the higher concentration of ADP, the better coagulation took place. Thrombin resulted in comparable coagulation at both 0.5 and 10% (w / v). Next, a blood clot which was obtained by incubating blood for 24 hours at 37° C. with 100 μg of AD...

example 3

Generation of an Acute Cerebral Trunk Arterial Embolus Model

[0045]As a study animal was utilized a male crab-eating macaque weighing about 6 kg. A sufficient amount of blood (1 ml) was drawn from the ventral tail artery of the animal with a syringe containing in advance ADP (a final concentration of 100 μg / ml) and thrombin (a final concentration of 10% (w / v)) as coagulants and filled immediately into a polyethylene tube (O.D.: 0.965 mm, I.D.: 0.58 mm). An embolus having a well-solidified state was formed by leaving the mixture of the blood and coagulants at 37° C. for 24 hours while keeping the mixture in the tube. Subsequently, a very fine catheter for cerebral angiography which was in conformity to an arterial diameter (3 French) was used and inserted through a sheath placed into femoral artery, so as to place the catheter in a targeted cerebral vessel (left middle cerebral artery). During that, the catheter was guided by using a high-resolution X-ray cerebral angiographic apparat...

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Abstract

The present invention relates to a method for generating a non-human model animal of an arterial occlusive disease, wherein the method is characterized in that an artery is occluded at a specific site by ligating it or with an autologous blood clot. In particular, the present invention relates to a method and a kit for generating a cardiac infarction model, as well as a cardiac infarction animal model obtained by employing the method or kit, characterized in that in a non-human experimental animal, a blood vessel is ligated downstream of an arterial site of the heart to be occluded, followed by occluding the artery at said site. In addition, the present invention also relates to a method and a system for generating a non-human animal model of arterial embolus, as well as an arterial embolus animal model obtained by employing the method or system, characterized by adding an coagulating agent to autologous blood to form an autologous blood clot and subsequently employing an angiographic apparatus in delivering the autologous blood clot into an artery.

Description

TECHNICAL FIELD[0001]The present invention relates to a method and a kit or a system for generating a model animal of an arterial occlusive disease, as well as an arterial embolus animal model obtained by the method or system. Specifically, the present invention relates to a method and a kit or a system for generating a non-human model animal of an arterial occlusive disease, as well as an arterial embolus animal model obtained by the method or system, characterized by occluding an artery at a specific site by ligating it or with an autologous blood clot.BACKGROUND ART[0002]In the past, a number of models of heart diseases such as cardiac infarction has been used in medical studies, for example, of the circulatory system and in organ transplantation, or alternatively in the development of medicaments for circulatory system diseases. Recently, these models of heart diseases also have become utilized in studies on regenerative medicine.[0003]Regarding conventional models of cardiac in...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A01K67/00
CPCA01K67/027A01K2227/106A01K2227/108A01K2267/0375A61B6/037A61B6/508A61B6/504A61B6/507A61K49/0008G09B23/306A61B6/486
Inventor TERAMOTO, NOBORUILDA, HIDEHIROHAYASHI, TAKUYAOHTA, YOICHIRO
Owner HEALTH SCI TECH TRANSFER CENT JAPAN HEALTH SCI FOUND
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